Aims: We are carrying out a population-based case-control study of facial clefts in Norway, where the rate of cleft lip and palate is one of the highest in the world. This study, which began in 1996 and will run through 2002, attempts to enroll all babies born in Norway with a cleft lip or palate. Mothers provide detailed information on occupational and other exposures to potentially toxic substances, as well as nutrition, personal habits and medical history. Control infants are selected randomly from all live births. In order to investigate possible genetic susceptibility to teratogens, biological samples (blood or cheek swabs) are collected from cases, controls, and their biological parents. When completed, this will be one of the largest and most comprehensive studies of this common birth defect ever conducted. Accomplishments: As we near the completion of Year 4, we have completed enrollment of more than 400 cases and nearly 500 controls. Enrollment rates are remarkably high, with participation by more than 90% of eligible cases and more than 80% of controls. In order to begin to explore genetic susceptibility, we have identified about 220 case-parent triads for DNA extraction and laboratory analysis. We will examine the role of TGF-alpha and its interaction with maternal cigarette smoking (as has been reported in preliminary studies elsewhere) and the role of MTHFR and its interaction with maternal folate consumption. Other important candidate genes include variants of MSX and TGF-beta. We will use new statistical methods that we developed and which are achieving widespread use by others.